Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3). In this Perspectives article, we review and synthesize these recent lines of evidence and propose a working nomenclature for SCLC subtypes defined by relative expression of these four factors. Defining the unique therapeutic vulnerabilities of these subtypes of SCLC should help to focus and accelerate therapeutic research, leading to rationally targeted approaches that may ultimately improve clinical outcomes for patients with this disease.
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The authors thank N. Rekhtman for insightful comment regarding pathological criteria for small cell lung cancer diagnosis. This work was supported by grants from the US National Institutes of Health, including U24CA213274 (C.M.R., J.T.P., A.D., J.D.M. and A.F.G.), R01CA197936 (C.M.R., J.T.P. and C.D.), R01CA207295 (L.A.B.), U01CA213273 (L.A.B., J.V.H. and J.S.), P50CA70907 and U01CA213338 (J.E.J., J.D.M. and A.F.G.), U54CA217450 (J.M.L. and V.Q.), UG1CA233259 (J.M.L.) and R21CA216504 (T.G.O.); by Veterans Affairs Merit Review I01CX001425 (P.P.M.); by a LUNGevity Foundation Career Development Award (J.M.L.); and by Cancer Research UK A27412, A25254 and A20465 (C.D.).
Nature Reviews Cancer thanks T. Bivona, E. Brambilla and other anonymous reviewer(s) for their contribution to the peer review of this work.
C.M.R. has consulted for AbbVie, Amgen, Ascentage, AstraZeneca, BMS, Celgene, Daiichi Sankyo, Genentech/Roche, Ipsen, Loxo and PharmaMar; is on the scientific advisory board for Elucida and Harpoon; and receives research funding from Daiichi Sankyo. L.A.B. has consulted for AbbVie, AstraZeneca, BerGenBio, Genmab and PharmaMar and receives research support from AbbVie, AstraZeneca, Genmab and Tolero. C.D. has consulted for AstraZeneca and Merck and receives research funding from AstraZeneca, Epigene, Amgen, FLX Bio, Menarini and Angel. J.V.H. has consulted for AstraZeneca, Boehringer Ingelheim, Exelixis, Genentech, GlaxoSmithKline, Guardant, Hengrui, Lilly, Novartis, Spectrum, EMD Serono and Synta; has received research support from AstraZeneca, Bayer, GlaxoSmithKline and Spectrum; and receives royalties and licensing fees from Spectrum. J.M.L. receives research funding from Ipsen and AbbVie. D.M. received research funding from Janssen and Roche. J.D.M. and A.F.G. receive licensing royalties for cell lines from the US National Institutes of Health and the University of Texas Southwestern Medical Center. J.S. receives research funding from AbbVie. C.R.V. is an adviser to KSQ Therapeutics. All other authors declare no competing interests.
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Rudin, C.M., Poirier, J.T., Byers, L.A. et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer 19, 289–297 (2019). https://doi.org/10.1038/s41568-019-0133-9
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